Pre-clinical Models of Odontic Analogs by Endogenous Stem Cells Project summary Tooth loss is the most common organ failure. Complete tooth loss in many wildlife species equates to the end of life. For humans, tooth loss negatively impacts one's self-esteem and impairs multiple physiological functions including mastication, digestion and/or speech. In this application that is specifically designed in response to PA-10-009, Bioengineering Research Grants (BRG), we propose to develop odontic analogs based on biomaterial scaffolds in the shape and dimensions of native tooth roots in a preclinical model. Currently, dentures or dental implants are the treatments of choice for patients who are partially or completely edentulous. However, a number of drawbacks are associated with dentures and dental implants, including failure, metal allergy and excessive cost. We demonstrate in our preliminary data that a tooth root analog regenerated with putative periodontal ligament and alveolar bone upon implantation of anatomically correct 3D biomaterial scaffold in vivo. The overall goal of this R01 proposal is to generate proof-of-concept data in a preclinical model that represents an obligatory step for further development of an affordable technology towards eventual clinical applications. As a departure from previous tooth regeneration studies that invariably involve the meritorious approach of stem cell transplantation, the proposed experiments are designed to include two primary innovative approaches. First, all the proposed studies will be based on the homing of host endogenous stem cells by cytotatic cues. No cells will be transplanted. Regeneration by stem cell homing, if proven effective in pre-clinical models and future clinical trials, may circumvent issues such as excessive time and cost in association with ex vivo cell culture, potential contamination and tumoerigenesis. Second, we take a novel approach to determine how physical properties of scaffold biomaterials affect the recruitment and differentiation of endogenous stem/progenitor cells, an approach that has not been investigated in tooth regeneration. If odontic analogs are developed in vivo as a function of various properties of bioscaffolds and without the delivery of cytotactic cues or cells, clinical translation can be further accelerated. These proposed studies in a preclinical model represent the most rigorous translational effort on tooth root regeneration, short of a human clinical trial that can only be conducted after a preclinical study and after FDA and IRB approvals.